Cap Assembly for a Medicament

ABSTRACT

An auto-injector for administering a dose of a liquid medicament includes an elongate housing arranged to contain a syringe with a hollow needle and a stopper for sealing the syringe and displacing the medicament, the housing having a distal end and a proximal end with an orifice intended to be applied against an injection site. The syringe is slidably arranged with respect to the housing. A spring capable of, upon activation: pushing the needle from a covered position inside the housing into an advanced position through the orifice and past the proximal end (P), operating the syringe to supply the dose of medicament (M), and retracting the syringe with the needle into the covered position. After delivering the medicament, an activator arranged to lock the spring in a pressurized state prior to manual operation and capable of, upon manual operation, releasing the spring for injection.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/276,366, filed Feb. 14, 2019, which is a continuation ofU.S. patent application Ser. No. 14/995,964, filed Jan. 14, 2016, nowPat. No. 10,232,116, which is a continuation of U.S. patent applicationSer. No. 13/579,435, filed Feb. 25, 2013, now Pat. No. 9,248,245, whichis a 35 U.S. C. 371 National Application of PCT/EP2011/052301, filedFeb. 16, 2011, and claims priority to European Patent Application No.10153999.7, filed Feb. 18, 2010 and U.S. Patent Application No.61/412,086, filed Nov. 10, 2010, the entire contents of which areincorporated entirely herein by reference.

TECHNICAL FIELD

The invention relates to an auto-injector for administering a dose of aliquid medicament according to the preamble of claim 1.

BACKGROUND OF THE INVENTION

Administering an injection is a process which presents a number of risksand challenges for users and healthcare professionals, both mental andphysical.

Injection devices (i.e. devices capable of delivering medicaments from amedication container) typically fall into two categories—manual devicesand auto-injectors.

In a manual device—the user must provide the mechanical energy to drivethe fluid through the needle. This is typically done by some form ofbutton/plunger that has to be continuously pressed by the user duringthe injection. There are numerous disadvantages to the user from thisapproach. If the user stops pressing the button/plunger then theinjection will also stop. This means that the user can deliver anunderdose if the device is not used properly (i.e. the plunger is notfully pressed to its end position). Injection forces may be too high forthe user, in particular if the patient is elderly or has dexterityproblems.

The extension of the button/plunger may be too great. Thus it can beinconvenient for the user to reach a fully extended button. Thecombination of injection force and button extension can cause trembling/ shaking of the hand which in turn increases discomfort as the insertedneedle moves.

Auto-injector devices aim to make self-administration of injectedtherapies easier for patients. Current therapies delivered by means ofself-administered injections include drugs for diabetes (both insulinand newer GLP-1 class drugs), migraine, hormone therapies,anticoagulants etc.

Auto-injectors are devices which completely or partially replaceactivities involved in parenteral drug delivery from standard syringes.These activities may include removal of a protective syringe cap,insertion of a needle into a patient's skin, injection of themedicament, removal of the needle, shielding of the needle andpreventing reuse of the device. This overcomes many of the disadvantagesof manual devices. Injection forces/button extension, hand-shaking andthe likelihood of delivering an incomplete dose are reduced. Triggeringmay be performed by numerous means, for example a trigger button or theaction of the needle reaching its injection depth. In some devices theenergy to deliver the fluid is provided by a spring.

US 2002/0095120 A1 discloses an automatic injection device whichautomatically injects a pre-measured quantity of fluid medicine when atension spring is released. The tension spring moves an ampoule and theinjection needle from a storage position to a deployed position when itis released. The content of the ampoule is thereafter expelled by thetension spring forcing a piston forward inside the ampoule. After thefluid medicine has been injected, torsion stored in the tension springis released and the injection needle is automatically retracted back toits original storage position.

US 2007/0112310 A1 discloses an injector being automatic in that theneedle is inserted into the injection site (e.g., a patient's skin) withuser or caregiver assistance, the delivery is automatically initiatedupon needle insertion, and the needle is retracted automatically afterthe end of delivery. Preferably the needle is not seen by the user priorto, during or after injection. Prior to and after injection, the needleis hidden in the device so as to avoid any potential injury or healthrisk to the user or health care provider. The injector includes ahousing and a shield arranged to slide relative to the housing and adriver moving during drug delivery. The housing and shield form acartridge enclosure. The cartridge is shielded and locked after deliveryis completed. A needle-locking mechanism can be used in any number ofpen-like injectors or safety needles.

U.S. Pat. No. 5,267,963 discloses an automatic injection device which,upon activation by the user, automatically extends a syringe withneedle, delivers medication through the needle, and retracts the needle,thus keeping the needle hidden from view. All motions are achieved bymeans of a tension spring and a cam profile.

WO 2009/081103 A1 discloses an auto-injector for a syringe that issuitable for use in the injected delivery of drug to a patient. Theauto-injector comprises a housing defining a housing cavity arranged forreceipt of a syringe; and a needle delivery aperture through which aneedle tip of the syringe protrudes during dispensing of the liquid drugformulation. The auto-injector further comprises a barrel couplingelement that couples to the barrel of the syringe and is movable intandem therewith; a syringe advancer for moving the syringe and barrelcoupling element in tandem therewith from a rest position, in which thehollow needle, is within the housing to a use position, in which theneedle tip protrudes through the needle delivery aperture; a syringeactuator for actuating the syringe by plunging said plunger within thebarrel of the syringe to dispense the liquid drug formulation; a syringeretractor for retracting the syringe and barrel coupling element intandem therewith from the use position to a retract position, in whichthe hollow needle is within the housing; and a syringe lock for lockingthe barrel coupling element and syringe coupled thereto in the retractposition.

WO 2008/155377 discloses an inserter for an infusion set comprising aninsertion needle and a spring unit assuring automatic insertion andautomatic retraction of the insertion needle. The inserter for a medicaldevice comprises—a housing, —a first body which is movable relative tothe housing and comprising penetrating means pointing in the directionof insertion, —a second body which is also movable relative to thehousing and —driving means which move respectively the first body andthe second body relative to the housing wherein the driving means movesthe first body in the direction of insertion and moves the second bodyin a direction different from the insertion direction.

DE 10 2005 038 933 A1 discloses an inserter for an infusion setcomprising an insertion needle and a spring unit assuring automaticinsertion and automatic retraction of the insertion needle. The inserterfor a medical device comprises—a housing, —a first body which is movablerelative to the housing and comprising penetrating means pointing in thedirection of insertion, —a second body which is also movable relative tothe housing and —driving means which move respectively the first bodyand the second body relative to the housing wherein the driving meansmoves the first body in the direction of insertion and moves the secondbody in a direction different from the insertion direction.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an improvedauto-injector.

The object is achieved by an auto-injector according to claim 1.

Preferred embodiments of the invention are given in the dependentclaims.

According to the invention, an auto- injector for administering a doseof a liquid medicament comprises:

-   -   an elongate housing arranged to contain a syringe with a hollow        needle and a stopper for sealing the syringe and displacing the        medicament, the housing having a distal end and a proximal end        with an orifice intended to be applied against an injection        site,

wherein the syringe is slidably arranged with respect to the housing,

-   -   spring means capable of, upon activation:        -   pushing the needle from a covered position inside the            housing into an advanced position through the orifice and            past the proximal end,        -   operating the syringe to supply the dose of medicament, and        -   retracting the syringe with the needle into the covered            position after delivering the medicament,    -   activating means arranged to lock the spring means in a        pressurized state prior to manual operation and capable of, upon        manual operation, releasing the spring means for injection.

In the context of this patent application the term proximal refers tothe direction pointing towards the patient during an injection while theterm distal refers to the opposite direction pointing away from thepatient.

According to the invention the spring means is a single compressionspring arranged to be grounded at a distal end in the housing foradvancing the needle and for injecting the dose of medicament. The forceof the compression spring is forwarded to the needle and/or the syringevia a plunger. The compression spring is arranged to have its ground inthe housing switched to its proximal end for retracting the syringe whenthe injection of the medicament is at least nearly finished.

The single compression spring is used for inserting the needle, fullyemptying the syringe and retracting the syringe and needle to a safeposition after injection. Thus a second spring for withdrawing thesyringe and needle, which is a motion with an opposite sense compared toadvancing the syringe and injecting the dose, is not required. While thedistal end of the compression spring is grounded the proximal end movesthe syringe forward for inserting the needle and carries on to theinjection by pushing on the stopper. When the injection is at leastnearly finished the compression spring bottoms out at its proximal end,resulting in the proximal end being grounded in the housing. At the sametime the distal end of the compression spring is released from itsground in the housing. The compression spring is now pulling the syringein the opposite direction.

The auto-injector according to the invention has a particularly low partcount compared to most conventional auto-injectors. The use of just onecompression spring reduces the amount of metal needed and thusconsequently reduces weight and manufacturing costs.

In a preferred embodiment of the invention a retraction sleeve isaxially movable arranged in the housing. At least one latch is providedfor axially fixing the retraction sleeve in a maximum proximal position.The compression spring is arranged inside the retraction sleeve with itsdistal end bearing against a distal end face of the retraction sleeveand with its proximal end bearing against a thrust face of a decouplingmember. The decoupling member is arranged to decouple the latch whenbeing moved in proximal direction nearly into a maximum proximalposition. When decoupled the retraction sleeve is allowed to move indistal direction and retract the needle by means of the spring forcewhich is no longer grounded at its distal end.

Preferably the plunger is arranged for pushing the syringe and/or thestopper in proximal direction. At least two resilient decoupling armsare arranged at the decoupling member. The decoupling arms exhibit innerramped surfaces bearing against a first shoulder of the plunger inproximal direction P. The resilient decoupling arms are supportable byan inner wall of the retraction sleeve in order to prevent thedecoupling arms from being flexed outward and slip past the firstshoulder. In this state the plunger may be pushed in proximal directionby the decoupling member pushing against the first shoulder in order toinsert the needle and inject the dose. At least one aperture is arrangedin the retraction sleeve allowing the decoupling arms to be flexedoutward by the first shoulder thus allowing the first shoulder to slipthrough the decoupling arms in proximal direction. This may happen whenthe injection is at least nearly finished. The decoupled plunger allowsthe syringe and needle to be retracted since it is no longer bearingagainst the decoupling member.

The syringe may be arranged for joint axial movement with a syringeholder which is slidably arranged in the retraction sleeve. The syringeholder is provided with at least two resilient syringe holder armsarranged distally, the syringe holder arms having a respective inclinedsurface for bearing against a second shoulder, which is arranged at theplunger proximally from the first shoulder. The syringe holder arms aresupportable by an inner surface of the housing in order to prevent themfrom being flexed outward. Thus, when the trigger button is pressed thespring force forwarded by the plunger does not yet press against thestopper but against the syringe for forwarding it. Consequently, a socalled wet injection is avoided, i.e. the liquid medicament is notleaking out of the hollow needle before the needle is inserted. Awidened portion is provided in the housing for allowing the syringeholder arms to flex outwards when the syringe holder has nearly reacheda maximum proximal position thus allowing the second shoulder to slipthrough the syringe holder arms and to switch load of the compressionspring from the syringe to the stopper. This allows for defining themoment to start injecting the medicament.

A stud may be arranged at the distal end of the plunger. The retractionsleeve may have two or more resilient arms distally from the end facefor holding the stud. The stud and/or the resilient arms have rampfeatures. Thus the resilient arms may be pushed apart by the stud whenthe plunger is moved in proximal direction. The activating meanscomprise a trigger button arranged at the distal end of theauto-injector. The trigger button is axially moveable and has at leasttwo rigid retainers for preventing the resilient arms from being flexedoutward when the trigger button is in a maximum distal position. Uponpushing the trigger button in proximal direction the retainers are movedin proximal direction in a manner to allow the resilient arms to beflexed out by the stud biased by the compression spring in proximaldirection. Thus the stud is allowed to slip past the resilient arms inproximal direction under load of the compression spring in order tostart a needle insertion/injection/retraction cycle. The main advantagesof this trigger mechanism are its simplicity, the low part count and ahigh reliability.

In order to reduce the risk of unintentionally triggering theauto-injector a safety button may be arranged laterally at the housing.The safety button has an interlock for preventing the trigger buttonfrom being pushed. The safety button is arranged to pull the interlockoutward when operated thus allowing the trigger button to be pushed. Forthis purpose the safety button may be pivoted in the housing or it maybe cast in one piece with the housing in a manner to be pivotedsomewhere in the middle so pushing one end inwards causes the other endto be pulled outwards.

Consequently, in order to operate the trigger button the safety buttonhas to be pushed first so the auto-injector cannot be operatedunintentionally. Another advantage of the lateral safety button is thatthe risk of operating the auto-injector in the wrong orientation andinjecting into the thumb is reduced.

In a preferred embodiment of the invention a delay box is arranged forslowing down the motion of the retraction sleeve. The latches arearranged to be disengaged by the decoupling member before the stopperhas reached a maximum proximal position in the syringe. The aperturesare arranged to meet the decoupling arms after the stopper has reachedits maximum proximal position by means of the motion of the retractionsleeve. A gap is provided between a front face of the retraction sleeveand the syringe holder in their respective maximum proximal positions.The gap allows the retraction sleeve to travel a distance beforeretracting the syringe holder so the syringe holder is retracted afterthe decoupling arms met the apertures.

Triggering the retraction when the stopper exactly reaches the end ofits travel is a problem due to tolerances when manufacturing the syringeand stopper. Due to these tolerances the position of the stopper at theend of its travel is not repeatable. Consequently, in some cases thestopper would prematurely bottom out so the retraction would not betriggered at all. In other cases the retraction would be triggeredbefore the stopper bottomed so residual medicament would remain in thesyringe.

Releasing the retraction sleeve from the housing a certain amount oftime or travel before the stopper bottoms out in the syringe avoids therisk of stalling the retraction by the stopper hitting the end of thesyringe prematurely. The damped backward motion of the retraction sleevedue to the delay box allows the plunger and stopper to finish theirforward travel so the syringe is entirely emptied. The apertures of theretraction sleeve and the decoupling arms, which are now moving inopposite directions, meet after the stopper and plunger have stopped inorder to decouple the decoupling member from the plunger. Due to the gapbetween the front face and the syringe holder the retraction sleeve isnot immediately dragging the syringe back in distal direction whenstarting to move back. When the retraction sleeve has travelled back farenough to close the gap the stopper has already bottomed out and theplunger has been decoupled from the decoupling member. As soon as thegap is closed the syringe holder, the syringe, the hollow needle and theplunger are dragged back in distal direction.

Thus both problems are solved, reliably retracting the hollow needle toa safe position and fully emptying the syringe which is particularlydesirable with expensive drugs. Emptying the syringe is also importantfor dosage accuracy.

The delay box may comprise a circumferential outer wall with a backcollar attached to the housing and a circumferential inner wall with afront collar attached to the retraction sleeve. A volume is definedbetween the outer wall and inner wall, the volume sealed by the backcollar and front collar and filled with a viscous fluid. At least onehole is arranged in the delay box for allowing the viscous fluid to bepushed out as the volume decreases due to motion of the retractionsleeve. This is a particularly simple and cost-efficient way to damp thebackward motion of the retraction sleeve.

Usually the hollow needle is equipped with a protective needle shieldfor keeping the needle sterile and preventing it from being mechanicallydamaged. The protective needle shield is attached to the needle when theauto-injector or the syringe is assembled.

Preferably a cap is provided at the proximal end of the housing. A sheetmetal clip is attached to the cap for joint axial movement andindependent rotation. The sheet metal clip is arranged to extend throughan orifice into the housing when the cap is attached to the housing. Thesheet metal clip comprises at least two barbs snapped into acircumferential notch or behind a shoulder of the protective needleshield. This allows for automatically engaging the sheet metal clip withthe protective needle shield during assembly. When the cap is removedfrom the housing in preparation of an injection the protective needleshield is reliably removed without exposing the user too high a risk toinjure themselves.

The cap may be attachable to the housing by a screw connection. Thisallows for a low force removal of the protective needle shield.

The housing may have at least one viewing window for inspecting thesyringe.

The auto-injector may preferably be used for subcutaneous orintra-muscular injection, particularly for delivering one of ananalgetic, an anticoagulant, insulin, an insulin derivate, heparin,Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine,antibodies and complex carbohydrates.

The term “medicament”, as used herein, means a pharmaceuticalformulation containing at least one pharmaceutically active compound,wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, a antibody, an enzyme, anantibody, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exedin-3 or exedin-4 or an analogue or derivative ofexedin-3 or exedin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(w-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(w-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

-   H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or-   des Pro36 [Asp28] Exendin-4(1-39),-   des Pro36 [IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),-   des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;

or an Exendin-4 derivative of the sequence

-   H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,-   des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,-   H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-Lys6-NH2,-   H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]    Exendin-4(1-39)-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]    Exendin-4(1-39)-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-NH2,-   des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,-   H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(S1-39)-(Lys)6-NH2,-   H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]    Exendin-4(1-39)-(Lys)6-NH2,

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exedin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCI or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

The delay box may be employed with other types of auto-injectors.

The cap with the sheet metal spring may also be applied with otherauto-injectors and injection devices.

Further scope of applicability of the present invention will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given herein below and the accompanying drawingswhich are given by way of illustration only, and thus, are not limitingof the present invention, and wherein:

FIG. 1 are two longitudinal sections of an auto-injector with a singlecompression spring for advancing a syringe with a needle, injecting adose of medicament and retracting the syringe and needle, theauto-injector as-delivered,

FIG. 2 are two longitudinal sections of the auto-injector with thesyringe and needle advanced and the dose expelled from the syringe,

FIG. 3 is a perspective sectional view of the auto-injector in theinitial state of FIG. 1,

FIG. 4 is another perspective sectional view of the auto-injector ofFIG. 3, and

FIG. 5 is a detail view of the distal end of the auto-injector with adelay box,

FIG. 6 is a detailed view of the proximal end of the autoinjectorshowing the cap and needle shield remover.

Corresponding parts are marked with the same reference symbols in allfigures.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

FIG. 1 shows two longitudinal sections in different section planes of anauto-injector 1, the different section planes approximately 90° rotatedto each other. The auto-injector 1 comprises an elongate housing 2. Asyringe 3, e.g. a Hypak syringe, with a hollow needle 4 is arranged in aproximal part of the auto-injector 1. When the auto-injector 1 or thesyringe 3 is assembled a protective needle shield 5 is attached to theneedle 4. A stopper 6 is arranged for sealing the syringe 3 distally andfor displacing a liquid medicament M through the hollow needle 4. Thesyringe 3 is held in a tubular syringe carrier 7 and supported at itsproximal end therein. A single compression spring 8 is arranged in adistal part of the auto-injector 1. A plunger 9 is arranged forforwarding the spring force of the compression spring 8.

Inside the housing 2 a retraction sleeve 10 is slidably arranged. Beforethe injection is triggered as shown in FIG. 1 the retraction sleeve 10is in a maximum proximal position and prevented from moving in distaldirection D by means of stops 11 caught behind latches 12 in the housing2. A distal end of the compression spring 8 bears against an end face 13of the retraction sleeve 10. Due to the stops 11 and latches 12 theforce of the compression spring 8 is thus reacted into the housing 2.The proximal end of the compression spring 8 bears against a decouplingmember 14 arranged around the plunger 9. Distally from the end face 13the retraction sleeve has two or more resilient arms 15 for holding astud 16 and keeping it from being moved in proximal direction P. Thestud 16 is arranged at the distal end of the plunger 9. The stud 16 andthe resilient arms 15 have corresponding ramp features for pushing theresilient arms 15 apart in order to allow the stud 16 and the plunger 9to move in proximal direction P.

The decoupling member 14 comprises a thrust face 17 for bearing againsta proximal end of the compression spring 8. Proximally from the thrustface 17 two or more resilient decoupling arms 18 are provided at thedecoupling member 14, the decoupling arms 18 having inner rampedsurfaces bearing against a first shoulder 19 in the plunger 9 inproximal direction P. The resilient decoupling arms 18 are supported byan inner wall of the retraction sleeve 10 in this situation so theycannot flex outward and slip past the first shoulder 19.

A trigger button 20 is arranged at the distal end D of the auto-injector1. The trigger button 20 may be pushed in proximal direction P in orderto start an injection. As long as the trigger button 20 is not pushedthe resilient arms 15 are caught between two or more retainers 21arranged at the trigger button 20 so the resilient arms 15 cannot flexoutward and the stud 16 although proximally biased by the compressionspring 8 cannot slip through.

The syringe carrier 7 is engaged for joint axial movement with a syringeholder 22 which is slidably arranged in the retraction sleeve 10. Thesyringe holder 22 is provided with two or more resilient syringe holderarms 23 arranged distally. The syringe holder arms 23 have a respectiveinclined surface for bearing against a second shoulder 24 in the plunger9 arranged proximally from the first shoulder 19. In the initialposition shown in FIG. 1 the syringe holder arms 23 are supported by aninner surface of the housing 2 so they cannot flex outward and thesecond shoulder 24 cannot slip through. In order to support the syringeholder arms 23 at the housing 2 a respective number of apertures areprovided in the retraction sleeve 10.

FIG. 1 shows the auto-injector 1 as-delivered with a cap 25 screwed ontoto the proximal end P of the auto-injector 1. FIG. 6 shows details ofthe proximal end P with the cap 25. The cap 25 comprises a sheet metalclip 26 with two or more barbs 27 extending through an orifice into theproximal end P of the auto-injector 1. The sheet metal clip 26 ismounted to the cap 25 for joint axial movement with respect to alongitudinal axis of the auto-injector 1. However, the sheet metal clip26 may rotate independently from the cap 25. This may be achieved byattaching the sheet metal clip 26 with a hole in its base onto a pinprotruding inwardly from the cap 25 and deforming the pin to form amushroom-shaped closing head 28 so as to prevent the sheet metal clip 26from being removed while allowing some clearance for the sheet metalclip 26 to rotate. When the cap 25 is screwed onto the proximal P end ofthe auto-injector 1 the barbs 27 are pushed down the protective needleshield 5 and snap into a circumferential notch arranged in theprotective needle shield 5 or behind a shoulder thereof.

When a user wants to operate the auto-injector 1 the first step is tounscrew the cap 25. Thus the barbs 27 pull the protective needle shield5 off the syringe 3 in proximal direction P and through the orificemaking the syringe 3 ready to be used.

A safety button 29 is arranged laterally at the distal part of thehousing 2. The safety button 29 serves for interlocking with the triggerbutton 20 in a manner to prevent the trigger button 20 from beinginadvertently operated without the safety button 29 being released froma first blocking position.

Consequently, in order to operate the trigger button 20 the safetybutton 29 has to be pushed transversally with respect to thelongitudinal axis against the force of a spring element 30 which isformed in the safety button 29. The safety button 29 is pivoted in themiddle so pushing the proximal end of the safety button 29 inward pullsan interlock 31 at its proximal end obstructing the trigger button 20outward so the trigger button 20 can be pushed.

When the trigger button 20 is pushed the retainers 21 are pushed inproximal direction P so the resilient arms 15 are allowed to flexoutward. Under load of the compression spring 8 the inclined surfaces ofthe stud 16 force the resilient arms 15 apart until the stud 16 can slipthrough.

The second shoulder 24 pushes the syringe holder 22, syringe carrier 7and syringe 3 forward while no load is exerted onto the stopper 6. Thehollow needle 4 appears from the proximal end P and is inserted into aninjection site, e.g. a patient's skin.

The forward movement continues until the syringe holder 22 bottoms outat a first abutment 32 in the housing 2 (see FIG. 2). The travel fromthe initial position (cf. FIG. 1) up to this point defines an injectiondepth, i.e. needle insertion depth.

When the syringe holder 22 has nearly bottomed out the resilient syringeholder arms 23 have reached a widened portion 2.1 of the housing 2 wherethey are no longer supported by the inner wall of the housing 2.However, since the force required to insert the needle 4 is relativelylow the second shoulder 24 will continue to drive forward the syringeholder 22 until proximal travel is halted at the first abutment 32. Atthis point the syringe holder arms 23 are flexed out by the continuedforce of the second shoulder 24 and allow it to slip through. Now theplunger 9 no longer pushes against the syringe holder 22 but against thestopper 6 for expelling the medicament M from the syringe 3 andinjecting it into or through the patient's skin.

When the stopper 6 has nearly bottomed out in the syringe 3 (cf. FIG. 2)the decoupling member 14 has reached a position where it pushes againstthe latches 12 in a manner to decouple the retraction sleeve 10 from thehousing 2, so the retraction sleeve 10 may slide in distal direction D.Thus the compression spring 8 is no longer grounded with its distal endin the housing 2. Instead, as soon as the decoupling member 14 hasbottomed out at a second abutment 33 the proximal end of the compressionspring 8 gets grounded in the housing while the distal end is pullingthe retraction sleeve 10 in distal direction D.

Just before the decoupling member 14 decouples the retraction sleeve 10from the housing 2 the decoupling arms 18 reach an aperture 34 in theretraction sleeve 10 (see FIG. 4) so they are no longer kept from beingflexed outward. The decoupling arms 18 are thus pushed outward by thefirst shoulder 19 pushing against its ramped surfaces so the firstshoulder 19 slips through in distal direction as soon as the decouplingmember 14 has hit the second abutment 33.

The syringe holder 22 is taken along in distal direction D by theretraction sleeve 10, e.g. by a front face 35. Thus the syringe 3 andneedle 4 are retracted into a safe position inside the housing 2, e.g.into the initial position. The plunger 9, no longer bearing against thedecoupling arms 18 is pulled back too.

In the distal part of the auto-injector 1 a delay box 36 is arranged(see FIG. 5 for details). The delay box 36 comprises a circumferentialouter wall 37 with a back collar 38 attached to the housing 2 and acircumferential inner wall 39 with a front collar 40 attached to theretraction sleeve 10. A volume between the outer wall 37 and inner wall39 is filled with a viscous fluid, such as silicon grease. As theretraction sleeve 10 is moved in distal direction D the inner wall 39glides along the outer wall 37 wherein the back collar 38 and frontcollar 40 increasingly reduce the volume. One or more holes (not shown)provided in a part of the delay box 36 allow the viscous fluid to bepushed out as the volume decreases. The force required to do this slowsdown the motion of the retraction sleeve 10.

The retraction sleeve 10 is released by the decoupling member 14 fromthe housing 2 a certain amount of time or travel before the stopper 6bottoms out in the syringe 3 and the distal motion of the retractionsleeve 10 begins. The motion of the retraction sleeve 10 is slowed downby the delay box 36. Due to a gap 41 between the front face 35 and thesyringe holder 22 the retraction sleeve 10 is not yet dragging thesyringe back in distal direction D. The plunger 9 is still pushingagainst the stopper 6 and expelling residual medicament M. As thestopper 6 hits the proximal end of the syringe 3 the stopper 6 andplunger 9 stop while the retraction sleeve 10 is still slowly movingback in distal direction D. The apertures 34 now meet the decouplingarms 18 allowing them to flex out and the plunger 9 to come clear. Theretraction sleeve 10 has now travelled back far enough to close the gap41 so the syringe holder 22, syringe carrier 7, syringe 3, needle 4 andplunger 9 are dragged back in distal direction D.

The cap 25 and the delay box 36 are not restricted to be used with theauto-injector 1 shown in the embodiments. Instead the cap 25 may becombined with any kind of auto-injector with the needle hidden in thehousing prior to an injection. The delay box may be combined with anykind of auto-injector for ensuring full delivery of the syringe'scontents and reliable triggering of the retraction, irrespective of thespring means or driving means used in the respective auto-injector.

The housing 2 may have at least one viewing window for inspecting thesyringe 3.

The auto-injector 1 may preferably be used for subcutaneous orintra-muscular injection, particularly for delivering one of ananalgetic, an anticoagulant, insulin, an insulin derivate, heparin,Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine,antibodies and complex carbohydrates.

The aforementioned arrangement for coupling the plunger (9) to either,the syringe (3) or the stopper (6), may be applied in any auto-injectorhaving a plunger for forwarding a force of a drive means to a syringewith a stopper. The primary advantage of this arrangement ensures theload from the drive means is not transferred directly to the stopperuntil the needle is inserted in the patient, thus avoiding a wetinjection. The arrangement comprises the syringe holder (22) andassociated syringe holder arms (23), a shoulder (e.g. the secondshoulder 24) on the plunger (9), the support of the holder arms (23) byan inner surface in order to prevent them from flexing out in a firstposition and, a widened portion (2.1) for allowing them to flex radiallyand to disconnect from the plunger when in a more proximal position. Thespring means or other drive means, the ability to retract the syringe orto forward a needle shroud after injection and other features describedherein are not required for the prevention of a wet injection.

List of References

1 auto-injector

2 housing

2.1 widened portion

3 syringe

4 hollow needle

5 protective needle shield

6 stopper

7 syringe carrier

8 spring means, compression spring

8.1 distal end

8.2 proximal end

9 plunger

10 retraction sleeve

11 stop

12 latch

13 end face

14 decoupling member

15 resilient arm

16 stud

17 thrust face

18 decoupling arm

19 first shoulder

20 activating means, trigger button

21 retainer

22 syringe holder

23 syringe holder arm

24 second shoulder

25 cap

26 sheet metal clip

27 barb

23 Attorney Docket No. 46567-0086004

28 closing head

29 safety button

30 spring element

31 interlock

32 first abutment

33 second abutment

34 aperture

35 front face

36 delay box

37 outer wall

38 back collar

39 inner wall

40 front collar

41 gap

D distal end, distal direction

M medicament

P proximal end, proximal direction

1. (canceled)
 2. A drug delivery device, comprising: an elongate member;a drug container with a needle arranged in the elongate member, theneedle having a proximal needle tip configured to pierce a skin at aninjection site; a needle shield configured to attach to the needle andcover the proximal needle tip; and a cap that is detachable from thedrug delivery device, the cap comprising a cap member providing an outersurface of the cap, wherein the outer surface is configured to bemanipulated by a user to detach the cap from the drug delivery device;and an interface member configured to engage the needle shield, theinterface member being axially locked to the cap member, and the capmember being rotatable relative to the interface member in order todetach the cap from the drug delivery device.
 3. The drug deliverydevice of claim 2, wherein a proximal end of the cap covers a proximalend of the needle shield.
 4. The drug delivery device of claim 2,wherein the needle shield is configured to be removed from the needlewhen the cap is detached from the drug delivery device.
 5. The drugdelivery device of claim 2, wherein the interface member is axiallylocked to the cap member such that relative axial movement between theinterface member and the outer surface is prevented.
 6. The drugdelivery device of claim 2, wherein the elongate member has a proximalend configured to contact the skin adjacent to the injection site. 7.The drug delivery device of claim 2, wherein the elongate member isconfigured to extend axially beyond the proximal needle tip when the capis detached.
 8. The drug delivery device of claim 2, wherein relativeaxial movement between the drug container and the elongate member isnecessary to pierce skin at the injection site.
 9. The drug deliverydevice of claim 2, wherein the cap is threadedly coupled to the elongatemember.
 10. The drug delivery device of claim 2, wherein the interfacemember comprises a sheet.
 11. The drug delivery device of claim 10,wherein the sheet is a metal sheet.
 12. The drug delivery device ofclaim 10, wherein the interface member comprises a plurality of barbs.13. The drug delivery device of claim 12, wherein the plurality of barbsare configured to engage the needle shield.
 14. The drug delivery deviceof claim 13, wherein the plurality of barbs are configured to engage theneedle shield between a proximal end of the needle shield and a distalend of the needle shield.
 15. The drug delivery device of claim 2,wherein the drug container is a syringe.
 16. The drug delivery device ofclaim 15, wherein the syringe is held in a syringe carrier and whereinthe syringe is supported at a proximal end of the syringe in the syringecarrier.
 17. The drug delivery device of claim 2, further comprising adrive spring and a plunger.
 18. The drug delivery device of claim 17,wherein the plunger is configured to transfer a spring force of thedrive spring to a movable stopper within the drug container to dispensea drug from the drug container.
 19. The drug delivery device of claim18, wherein the drive spring is arranged in a distal part of drugdelivery device.
 20. The drug delivery device of claim 18, wherein thedrug delivery device is an auto-injector.